For the use only of Registered Medical Practitioners or a Hospital or a Laboratory KEMADRIN TABLETS. Procyclidine Tablets IP 2.

Transcription

1 For the use only of Registered Medical Practitioners or a Hospital or a Laboratory KEMADRIN TABLETS Procyclidine Tablets IP 2.5 mg and 5 mg QUALITATIVE AND QUANTITATIVE COMPOSITION KEMADRIN TABLETS 2.5 MG Each uncoated tablet contains Procyclidine Hydrochloride IP 2.5 mg. KEMADRIN TABLETS 5 MG Each uncoated tablet contains Procyclidine Hydrochloride IP 5 mg. PHARMACEUTICAL FORM Uncoated tablet. CLINICAL PARTICULARS Therapeutic Indications KEMADRIN is indicated for: the treatment and symptomatic relief of all forms of Parkinson's disease e.g. idiopathic (paralysis agitans), postencephalitic and arteriosclerotic disease; procyclidine is efficacious in the relief of parkinsonian symptoms. Procyclidine is particularly effective in the alleviation of rigidity. Tremor, akinesia, speech and writing difficulties, gait, sialorrhoea and drooling, sweating, oculogyric crises and depressed mood are also beneficially influenced. the control of extrapyramidal symptoms induced by neuroleptic drugs including pseudoparkinsonism, acute dystonic reactions and akathisia. Posology and Method of Administration Pharmacokinetic studies have indicated that the mean plasma elimination half-life of procyclidine is sufficient to allow twice daily administration. Oral administration may be better tolerated if associated with a meal. Tablets can be divided into equal doses. The variation in optimum dosage from one patient to another should be taken into consideration by the physician. Route of Administration For oral use. 1

2 Adults Parkinson's disease Treatment is usually started at 2.5mg KEMADRIN three times per day, increasing by 2.5mg to 5mg per day at intervals of two or three days until the optimum clinical response is achieved. The usual maintenance dose to achieve optimal response is 15 to 30mg KEMADRIN per day. Addition of a fourth dose before retiring has been seen to be beneficial in some patients. Doses up to 60mg procyclidine have been well tolerated, and at the discretion of the attending physician dosing to this level may be appropriate. In general younger patients or those with postencephalitic parkinsonism may require higher doses for a therapeutic response than older patients and those with arteriosclerotic parkinsonism. KEMADRIN may be combined with levodopa or amantadine in patients who are inadequately controlled on a single agent. Neuroleptic-induced extrapyramidal symptoms Treatment is usually initiated at 2.5mg KEMADRIN three times per day increasing by 2.5mg daily until symptoms are relieved. The effective maintenance dose is usually 10 to 30mg KEMADRIN per day. After a period of 3 to 4 months of therapy, KEMADRIN should be withdrawn and the patient observed to see whether the neuroleptic-induced extra-pyramidal symptoms recur. If this is the case KEMADRIN should be reintroduced to avoid debilitating extra-pyramidal symptoms. Cessation of treatment periodically is to be recommended even in patients who appear to require the drug for longer periods. Children The use of KEMADRIN in this age group is not recommended. Elderly Elderly patients, especially those on high doses of anticholinergics may be more susceptible to the adverse events associated with such therapy. (see Special Warnings and Special Precautions for Use). Renal and hepatic impairment Since procyclidine is metabolised in the liver and excreted via the urine care should be exercised when administering KEMADRIN to patients with impairment of renal or hepatic function (see Special Warnings and Special Precautions for use). Contraindications 2

3 KEMADRIN is contraindicated in: known hypersensitivity to any component of the preparation, untreated urinary retention, closed angle glaucoma, gastro-intestinal obstruction. Special Warnings and Special Precautions for Use Eye disorders As with all anticholinergics the benefit/risk ratio should be assessed when prescribing KEMADRIN in patients with existing angle-closure (narrow angle) glaucoma or those considered to be predisposed to glaucoma. Obstructive disease of the gastro-intestinal tract Cautious prescribing is indicated in patients predisposed to obstructive disease of the gastrointestinal tract. Prostatic hypertrophy Cautious prescribing is indicated in patients with urinary symptoms associated with prostatic hypertrophy. Tardive dysknesias In a proportion of patients undergoing neuroleptic treatment, tardive dysknesias will occur. While anticholinergic agents do not cause this syndrome, when given in combination with neuroleptics they may exacerbate the symptoms of tardive dyskinesia or reduce the threshold at which these symptoms appear in predisposed patients. In such individuals subsequent adjustment of neuroleptic therapy or reduction in anticholinergic treatment should be considered. Precipitation of a psychotic episode Patients with mental disorders occasionally experience a precipitation of a psychotic episode when procyclidine is administered for the treatment of the extrapyramidal side effects of neuroleptics (see Undersirable Effects). Elderly patients Elderly patients, especially those on high doses of anticholinergics may be more susceptible to the adverse events associated with such therapy. Specifically, the elderly patient may be particularly vulnerable to Central Nervous System disturbances such as confusion, impairment of cognitive function and memory, disorientation and hallucinations (see Undersirable Effects). These effects are usually reversible on reduction or discontinuation of anticholinergic therapy. Renal and hepatic impairment 3

4 There is no specific information available concerning the use of procyclidine hydrochloride in patients with impaired renal or hepatic function. However, since procyclidine is metabolised in the liver and excreted via the urine care should be exercised when administering KEMADRIN to patients with impairment of renal or hepatic function. Withdrawal therapy KEMADRIN should not be withdrawn abruptly as rebound parkinsonian symptoms may occur. Abuse KEMADRIN, along with other anticholinergic drugs, has the potential to be abused. Although the cases of abuse are rare, physicians should exercise caution in prescribing KEMADRIN to patients with symptoms that may not be genuine (see Overdose). Interaction with Other Medicaments and Other Forms of Interaction Drugs with anticholinergic properties Monoamine oxidase inhibitors or drugs with anticholinergic properties, such as amantadine, memantine, antihistamines, phenothiazines, tricyclic and related antidepressants, clozapine, disopyramide and nefopam may increase the anticholinergic action of KEMADRIN. Drugs with cholinergic properties The use of drugs with cholinergic properties, such as tacrine, may reduce the therapeutic response to KEMADRIN. Furthermore, drugs with anticholinergic properties may antagonise the effect of parasympathomimetic agents. Neuroleptics The concomitant use of procyclidine with some neuroleptics for the treatment of extrapyramidal symptoms has been associated with a reduction in neuroleptic plasma concentrations. However this reduction is unlikely to be associated with a significant reduction in clinical effect. Sublingual or buccal forms of nitrates Drugs with anticholinergic properties may decrease salivation causing dry mouth and, in theory, may reduce the absorption and therefore the therapeutic effect of sublingual or buccal nitrate tablets. Levodopa Anticholinergics, including KEMADRIN, may reduce the efficacy of levodopa by increasing gastric emptying time, resulting in enhanced gastric degradation. Cisapride, domperidone and metoclopramide 4

5 The effect of anticholinergics such as KEMADRIN may antagonise the gastrointestinal effects of cisapride, domperidone and metoclopramide. Quinidine KEMADRIN may potentiate the vagolytic effects of quinidine. Ketoconazole Anticholinergics such as KEMADRIN may reduce the absorption of ketoconazole. Phenothiazine/anticholinergic drugs Exposure to high environmental temperature and humidity in association with a phenothiazine/anticholinergic drug regimen has rarely resulted in hyperpyrexia. Paroxetine Daily administration of paroxetine increases significantly the plasma levels of procyclidine. If anticholinergic effects are seen, the dose of KEMADRIN should be reduced. Pregnancy and Lactation Fertility There are no relevant data available. Pregnancy As with all drugs, use of KEMADRIN should be considered only when the expected clinical benefit of treatment for the mother outweighs any possible risk to the developing foetus. The safety of using procyclidine during pregnancy has not been established. However, extensive clinical use has not given any evidence that it in any way compromises the normal course of pregnancy. Lactation No information is available on the passage of procyclidine into human breast milk. Effects on Ability to Drive and Use Machines Adverse events of a neurological character such as blurred vision, dizziness, confusion and disorientation have been reported with procyclidine. Therefore if affected, patients should be advised not to drive or operate machinery. Undesirable Effects 5

6 Clinical Trial and Post Marketing Data The main undesirable effects are those to be expected from any anticholinergic agent these are generally reversible on reducing the dosage. With high doses of procyclidine dizziness, mental confusion, impaired cognition and memory, disorientation, anxiety, agitation and hallucinations may occur. Adverse drug reactions (ADRs) are listed below by MedDRA system organ class and by frequency. Frequencies are defined as: Very common 1/10 Common 1/100 to <1/10 Uncommon 1/1000 to <1/100 Rare 1/10000 to <1/1000 Very rare <1/10000 Not known (cannot be estimated from the available data). Psychiatric disorders Uncommon: agitation, anxiety, nervousness, confusion, disorientation, hallucinations. Rare: psychotic disorder. Nervous system disorders Uncommon: dizziness, memory impairment, impaired cognition. Eye disorders Common: blurred vision. Gastrointestinal disorders Common: dry mouth, constipation. Uncommon: nausea, vomiting, gingivitis. Skin and subcutaneous tissue disorders Uncommon: rash. Renal and urinary disorders Common: urinary retention. Overdose Symptoms and Signs Symptoms of overdosage include stimulant effects such as agitation, restlessness and confusion with severe sleeplessness lasting up to 24 hours or more. 6

7 Visual and auditory hallucinations have been reported. Most subjects are euphoric but the occasional patient may be anxious and aggressive. The pupils are widely dilated and unreactive to light. In recorded cases, the disorientation has lasted 1 to 4 days and ended in a recuperative sleep. Signs of central nervous system (CNS) depression including somnolence, reduced consciousness, and occasionally coma have been reported usually following very large overdoses. Tachycardia has also been reported in association with cases of procyclidine overdose. Treatment If KEMADRIN has been ingested within the previous hour or two (or possibly longer in view of its likely effects on gastric motility) then activated charcoal should be used to reduce absorption. Other active measures such as the use of cholinergic agents or haemodialysis are extremely unlikely to be of clinical value although if convulsions occur they should be controlled by injections of diazepam. Further management should be as clinically indicated or as recommended by the national poisons centre, where available. PHARMACOLOGICAL PROPERTIES Pharmacodynamic Properties Pharmacotherapeutic group: Anti-parkinson drug, anticholinergic agent; ATC Code: N04AA04. Mechanism of Action and Pharmacodynamic effects Procyclidine is a synthetic anticholinergic agent which blocks the excitatory effects of acetylcholine at the muscarinic receptor. Idiopathic Parkinson's disease is thought to result from degeneration of neurones in the substantia nigra whose axons project and inhibit cells in the corpus striatum. Blockade by neuroleptic drugs of the dopamine released by these terminals produces a similar clinical picture. The cell bodies in the corpus striatum also receive cholinergic innervation which is excitatory. Relief of the Parkinsonian syndrome can be achieved, either by potentiation of the dopaminergic system or blockade of the cholinergic input by anticholinergics. It is by a central action of this latter type by which Procyclidine exerts its effect. Procyclidine is particularly effective in the alleviation of rigidity. Tremor, akinesia, speech and writing difficulties, gait, sialorrhoea and drooling, sweating, oculogyric crises and depressed mood are also beneficially influenced. Pharmacokinetic Properties 7

8 Absorption Procyclidine is adequately absorbed from the gastrointestinal tract with a bioavailability of 75%. Distribution Procyclidine disappears rapidly from the tissues. Metabolism and Elimination The relatively low clearance of 68 ml/min represents a predominantly metabolic change with a small first pass effect. The mean plasma disappearance half-life after oral administration is approximately 12 h. No detailed information is available on the metabolic fate of procyclidine but very little of the parent compound is excreted in the urine unchanged. When given orally about one fifth of the dose is known to be metabolised in the liver, principally by cytochrome P450 and then conjugated with glucuronic acid. This conjugate has been detected in the urine. Clinical Studies Not relevant for this product. Preclinical Safety Data Fertility A three generation study in rats dosed at 40 mg/kg/day via the diet before and during pregnancy showed only that the number of available pups was slightly decreased from the second mating. No other parameters were affected. Teratogenicity No teratogenic effects were seen in rats dosed subcutaneously with 10, 30 or 100 mg/kg/day on days 8 to 16 of pregnancy. Maternal bodyweight gain was reduced at doses of 30 or 100 mg/kg/day, and a 10% reduction in foetal weight was seen at 100 mg/kg/day. Mutagenicity Procyclidine was not genotoxic in in-vitro bacterial mutation or mouse lymphoma assays. Carcinogenicity There are no data on the carcinogenic potential of procyclidine hydrochloride. PHARMACEUTICAL PARTICULARS 8

9 List of Excipients Lactose, sodium starch glycollate, polyvinyl pyrrolidone K-30 and magnesium stearate. Incompatibilities No incompatibilities have been identified. Shelf Life 36 months The expiry date is indicated on the label and packaging. Special Precautions for Storage Store at a temperature not exceeding 30 o C. Keep out of reach of children. Nature and Specification of Container Strips of tablets in a carton. All pack presentations may not be marketed in the country. Instructions for Use / Handling There are no special requirements for use or handling of this product. For further information please contact: GlaxoSmithKline Pharmaceuticals Limited. Registered Office Dr. Annie Besant Road, Worli, Mumbai , India. KEMADRIN is a Registered Trademark of GSK group of companies. Version: KEM/PI/IN/2017/01 dated 12 Apr Adapted from Procyclidine Hydrochloride NCDS version 02 dated 18 January